Evaluation of Clostridium difficile-Associated Diarrhea With a Drug Formulary Change in Preferred Fluoroquinolones

BACKGROUND: Recent publications report that gatifloxacin might be associated with a greater incidence of Clostridium difficile-associated diarrhea (C. difficile, CDAD) than are other fluoroquinolones. We performed a drug use evaluation to examine this issue after adding gatifloxacin to the formulary and changing from levofloxacin to gatifloxacin as the preferred oral fluoroquinolone in 10 Department of Veterans Affairs (VA) medical centers in the northeastern United States. OBJECTIVES: To estimate (1) the overall incidence of CDAD before and after the change from levofloxacin to gatifloxacin as the preferred oral fluoroquinolone and (2) the incidence rates for ciprofloxacin, levofloxacin, and gatifloxacin separately. METHODS: Using the VA's Pharmacy Benefits Management database, the total number of days of antibiotic therapy was determined for all inpatients and outpatients of the 10 medical centers who filled at least 1 antibiotic prescription between July 1, 2003, and June 30, 2004. This time frame was chosen because it included 6 months before and 6 months after the change in the preferred oral fluoroquinolone from levofloxacin to gatifloxacin for the VA health system on January 1, 2004. For the same study period and medical centers, the electronic medical records of all inpatients and outpatients with an entry for a positive C. difficile toxin were reviewed. Positive toxins that occurred within 6 weeks of a previous positive result in the same patient were excluded. Exact Poisson tests were used to compare the incidence rates of CDAD (number of CDAD cases per 1,000 days of antibiotic treatment) for antibiotics overall, the fluoroquinolones as a group, non-fluoroquinolone antibiotics, and the individual fluoroquinolones, com-paring the 6-month time periods before (pre-change) versus after (post-change) the addition of gatifloxacin as the preferred oral fluoroquinolone. RESULTS: Of 505 cases of CDAD in the 12-month study period, 413 (81.7%) were associated with antibiotic use in the previous 6 weeks. Among anti-biotic users, incidence rates of CDAD were 166 per 72,114 days of antibiotic therapy in the pre-change period (2.3 cases per 1,000 days of antibiotics) versus 247 per 72,354 days in the post-change period (3.4 cases per 1,000 days of antibiotics, P less than 0.001). Fluoroquinolones accounted for 54.8% of the CDAD cases in the pre-change period and 67.2% in the post-change period, representing a 22.6% relative increase in the percentage of CDAD cases that were associated with fluoroquinolone use. The CDAD incidence rates per 1,000 days of fluoroquinolone therapy were 3.7 in the pre-change period versus 7.0 in the post-change period (P less than 0.001). Among fluoroquinolone users, gatifloxacin accounted for none of the cases of CDAD in the pre-change period when it was nonformulary and 65.1% of the cases in the post-change period, for an incidence rate of 7.6 (108 per 14,239 days). The CDAD incidence rates per 1,000 antibiotic days for patients treated with ciprofloxacin were 4.6 (24 per 5,260 days) in the pre-change period and 7.4 (40 per 5,429 days) in the post-change period, a nonsignificant trend (P = 0.079). The incidence rate of CDAD for levofloxacin increased significantly from 3.9 (75 per 19,417 days) in the pre-change period to 10.7 (44 per 4,108 days) in the post-change period (P less than 0.001). The incidence rates of CDAD in the post-change period did not differ significantly for ciprofloxacin, levofloxacin, and gatifloxacin (P = 0.119). CONCLUSIONS: There was an increase in the incidence of CDAD among all antibiotic users and fluoroquinolone users, but not among users of non-fluoroquinolone antibiotics, in the period following the formulary change from levofloxacin to gatifloxacin as the preferred fluoroquinolone. However, rates of CDAD among the 3 fluoroquinolone antibiotics in the post-change period were not significantly different, and levofloxacin was the only fluoroquinolone that was associated with a significant�

• In studies of outbreaks of Clostridium difficile-associated diarrhea (CDAD) with increasing virulence, fluoroquinolones have been identified as a risk factor for the development of the infection. Because of its extended antimicrobial spectrum, which includes enhanced anaerobic coverage, there are concerns that gatifloxacin, in particular, may be associated with an increased incidence of CDAD.
• Although we found an increase in the incidence of CDAD after changing to gatifloxacin as the preferred oral formulary fluoroquinolone, the CDAD incidence rates for gatifloxacin, ciprofloxacin, and levofloxacin were not significantly different. This finding suggests that the increase was probably not attributable to the formulary change. • Because simple pre-versus post-drug use evaluations may produce confusing results, more detailed patient-level analyses are necessary to assess the impact of formulary changes.
of CDAD have increased over the past 2 decades, 4 resulting in extended hospitalizations, increased health care costs, and poor outcomes. The major risk factor for developing CDAD continues to be the recent use of antibiotics. 5 Earlier reports of CDAD implicated clindamycin, cephalosporins, and ampicillin. 6 However, since the fluoroquinolone antibiotics have become widely prescribed, there have been case reports and observational studies linking them with CDAD. [7][8][9][10][11][12] In addition, several studies specifically found an association between prior levofloxacin and gatifloxacin use and an increased incidence of CDAD. 7,8,10,13 In a case-control study conducted by Gaynes et al. in a long-term care facility, the attack rate for CDAD was 17% when levofloxacin was on the formulary versus 30% after the change to gatifloxacin (P < 0.02). 8 The rate declined when the preferred fluoroquinolone was changed back to levofloxacin. In their multivariable analysis, the number of days of gatifloxacin therapy was independently associated with CDAD (P < 0.0001). However, a correspondence by Mohr emphasizes that the authors did not account for infection control measures that were instituted just prior to changing back to levofloxacin. 13 In contrast with the study by Gaynes et al., an analysis by Muto et al. found an association between the use of levofloxacin and CDAD at a community-based hospital. 10 Similarly, Changela et al. found that prior use of levofloxacin was a risk factor for the development of CDAD among hospitalized veterans. 7 Finally, recent reports have documented widespread outbreaks of CDAD with increased virulence, leading to a higher proportion of colectomies and deaths. 14,15 Prior exposure to a fluoroquinolone was a significant risk factor for acquisition of the infection, 10,14,15 with an odds ratio (OR) of 3.9 (95% confidence interval [CI], 2.3-6.6) in one of the studies. 14 Prior to January 2004, the only fluoroquinolones available in the Department of Veterans Affairs (VA) formulary were ciprofloxacin and levofloxacin. On January 1, 2004, gatifloxacin was added to the formulary and replaced levofloxacin as the preferred oral fluoroquinolone. In response to internal concerns that gatifloxacin might be associated with a greater incidence of CDAD than other fluoroquinolones because of its broader spectrum of activity that includes enhanced anaerobic coverage, 8 we performed a drug use evaluation (DUE) to estimate the incidence of CDAD before and after the change to gatifloxacin as the preferred oral fluoroquinolone within a group of VA medical centers in the northeastern United States. On February 15, 2006, the U.S. Food and Drug Administration issued a warning regarding severe hypoglycemia and hyperglycemia associated with gatifloxacin and its contraindication in patients with diabetes. In response to this warning, Bristol-Myers Squibb, the manufacturer of gati floxacin, voluntarily withdrew the antibiotic from the market effective June 2, 2006. Although gatifloxacin is no longer available, concerns remain that fluoroquinolones may play a major role in the development of CDAD and that specific fluoroquinolones may be associated with a greater risk of CDAD. 10,16 ■■ Methods The study consisted of (1) an assessment of the incidence rates of CDAD per 1,000 days of antibiotic therapy and (2) a retrospective electronic medical record review of patients with a positive C. difficile toxin. The Drug Use Evaluation Subcommittee of the Pharmacy and Therapeutics (P&T) Committee at the VA Pittsburgh Healthcare System (VAPHS) developed the assessment protocol in cooperation with the regional VA P&T committee. Exempt status was granted by the VAPHS Institutional Review Board because this was a quality assurance project for the VA Center for Medication Safety.

Patient Eligibility
Study subjects were patients of 10 VAPHS medical centers in Pennsylvania, Delaware, and northern West Virginia. To provide a denominator for the assessment of incidence rates, the total number of days of antibiotic therapy for all inpatients and outpatients who filled at least 1 antibiotic prescription between July 1, 2003, and June 30, 2004, were identified using the VA's Pharmacy Benefits Management database. This time frame was chosen because it included 6 months before and 6 months after the switch from levofloxacin to gatifloxacin as the preferred oral fluoroquinolone for the VA health system on January 1, 2004.
For the same study period and medical centers, all inpatients and outpatients with a positive C. difficile toxin between July 1, 2003, and June 30, 2004, were identified using the VAPHS electronic medical record. Patients could be included more than once during the study period; however, repeat positive toxins that occurred within 6 weeks of a previous event in the same patient were excluded to eliminate any confusion regarding classification (recurrence vs. reinfection). Patients were also excluded if their electronic medical records could not be accessed through the VAPHS.

Data Collection
For the incidence rate analysis, data collection included the total numbers of days of antibiotic therapy, overall and by antibiotic agent, for all patients receiving antibiotics during the review period. For the review of CDAD cases, data collection included demographics, signs and symptoms of infection with C. difficile, treatments, outcomes (i.e., infection resolved, surgical intervention required, or death), inpatient and outpatient antibiotic use within 6 weeks prior to the date of the positive toxin, and the setting in which the infection developed (i.e., outpatient vs. inpatient).

Analysis
Exact Poisson tests were used to assess changes in the CDAD incidence rates before and after the change to gatifloxacin as the preferred oral fluoroquinolone. Analyses were done separately for all antibiotics, the fluoroquinolones as a group, nonfluoroquinolone antibiotics, and the individual fluoroquinolones.
Exact Poisson tests and 95% CIs were used because some numerators were small. 17 To describe the change in incidence rates over time, we calculated exact Poisson tests and CIs for the rate ratios using exact Poisson regression in LogXact version 8. 18 Poisson regression is a generalization of linear regression when the outcome is a rate (i.e., count/person-time). 19 We estimated the rate ratios by fitting models of the form log (rate) = B 0 + B 1 *X, where X = 1 for the post-period and 0 for the pre-period. The estimated rate ratio comparing the CDAD rate for a particular antibiotic in the post-change period versus the pre-change period is exp (B 1 ). We also compared the CDAD incidence rates for the 3 fluoroquinolones in the post-period using a Poisson regression model of the form log (rate) = B 0 + B 1 * X 1 + B 2 * X 2 , where X 1 and X 2 are indicator variables denoting levofloxacin and gatifloxacin, respectively. An overall test of the null hypothesis that the 3 rates are the same was obtained by testing B 1 = B 2 =0 in this model. A 2-sided P value < 0.05 was considered to be statistically significant. In the analyses of the individual fluoroquinolones, cases of CDAD were counted under each antibiotic received (e.g., ciprofloxacin and gatifloxacin) if the patient received more than 1 fluoroquinolone within the 6 weeks preceding the event.

■■ Results
Throughout the 10 facilities evaluated, 559 cases of CDAD were identified between July 1, 2003, and June 30, 2004. Of the identified cases, 42 were excluded because the positive toxin occurred within 6 weeks of a previous event. Finally, 12 cases were excluded because the medical records were not accessible, leaving 505 cases of CDAD during the study period. These cases occurred in 460 unique patients.
Among these patients with CDAD, 444 (96.5%) were male and the mean age was 69.2 years (SD 12.9). Most of the 460 patients accounted for a single case of CDAD during the study period (n = 420). However, 35 patients had 2 episodes of CDAD > 6 weeks apart, and 5 patients had 3 episodes of CDAD > 6 weeks apart. Table 1 describes the characteristics of the cases of CDAD before and after the formulary change to gatifloxacin. Among those episodes involving antibiotics, the average number of previous and/or concurrent antibiotics per episode within 6 weeks prior to the positive toxin was 2.9 (SD 1.7) in both time frames. There were 40 cases of CDAD (19.4%) that involved no documented receipt of prior antibiotics in the pre-change period compared with 52 cases (17.4%) in the post-change period.
Among the 413 episodes involving antibiotics (in 374 patients), the overall CDAD incidence rate increased significantly after the formulary change, from 166 per 72,114 days in the pre-change period (a rate of 2.3 cases per 1,000 days of antibiotics) to 247 per 72,354 days in the post-change period (a rate of 3.4 cases per 1,000 days of antibiotics), P < 0.001 ( Table 2). The incidence rate associated with the fluoroquinolones (i.e., ciprofloxacin, levofloxacin, and gatifloxacin) also increased significantly (P < 0.001). Among fluoroquinolone users, rates of CDAD per 1,000 days of antibiotic treatment were 3.7 in the pre-change period (91 per 24,708 days) and 7.0 in the post-change period (166 per 23,776 days). Fluoroquinolones accounted for 54.8% of the CDAD cases in the pre-change period and 67.2% in the postchange period, a change that represents a 22.6% relative increase in the percentage of CDAD cases that were associated with fluoroquinolone use. No significant change over time was seen in the incidence rates associated with non-fluoroquinolone antibiotics (1.6 vs. 1.7 per 1,000 days; P = 0.805).
The increased incidence of CDAD in the time period after the formulary switch to gatifloxacin was significant for levofloxacin (P < 0.001) but not for ciprofloxacin (P = 0.079). The CDAD incidence rate for patients treated with ciprofloxacin increased from 4.6 (24 per 5,260 days) in the pre-change period to 7.4 (40 per 5,429 days) in the post-change period, but the incidence of CDAD for levofloxacin increased from 3.9 (75 per 19,417 days) in the pre-change period to 10.7 (44 per 4,108 days) in the postchange period. There were no cases of CDAD among patients who received gatifloxacin when it was nonformulary, although there was some limited use of the antibiotic. After gatifloxacin was added to the formulary, there were 108 cases, for an incidence rate of 7.6 cases per 1,000 days of antibiotics. The change in incidence between the 2 time periods was not statistically significant (P = 0.628); however, this comparison is limited by the vast uncertainty in the pre-change rate for gatifloxacin. The CDAD incidence rates did not differ significantly among patients who received ciprofloxacin, levofloxacin, or gatifloxacin in the post-change period (P = 0.119, data not shown in table). The rate ratios, describing the change in incidence rates over time, were statistically significant for patients receiving any antibiotic (1.5; 95% CI, 1.2-1.8), the fluoroquinolones as a group (1.9; 95% CI, 1.5-2.5), and levofloxacin (2.7; 95% CI, 1.9-4.1).

■■ Discussion
The increased use of fluoroquinolones has been a concern because it promotes the emergence and spread of fluoroquinolone-resistant bacteria, including Streptococcus pneumoniae, Enterobacteriaceae, and Pseudomonas aeruginosa. [20][21][22][23][24] Now, outbreaks of CDAD caused by a strain associated with high morbidity, mortality, and fluoroquinolone resistance 11,14,15 have led to additional focus on appropriate antibiotic use and efforts to improve infection prevention measures.
Clindamycin, ampicillin, and cephalosporins are frequently associated with CDAD, but essentially all antibiotics have been reported to cause the infection. 3,6 Although the fluoroquinolones have been considered relatively low risk for causing CDAD,

Incidence Rates of Clostridium difficile-Associated Diarrhea (Cases per 1,000 Days of Antibiotics) Before and After Formulary Change to Gatifloxacin Among Patients Receiving Antibiotics
it is difficult to ascertain a difference in the incidence rate of CDAD among antibiotics because, to our knowledge, no large prospective studies have been conducted. 3,4 Even if their relative risk is comparatively low, the overall incidence will increase as fluoroquinolone prescribing increases. A number of recent retrospective case-control and cohort studies have reported an independent association between prior fluoroquinolone usespecifically, cipro floxacin, levofloxacin, and gatifloxacin-and the development of CDAD. [8][9][10][11][12] In some of these studies, increased fluoroquinolone use was reported. [9][10][11] In our evaluation, the overall incidence of CDAD increased after the change to gatifloxacin as the preferred oral fluoroquinolone among patients receiving antibiotics. In addition, the incidence rate increased among patients receiving any of the fluoro quinolones. However, in the post-change period, the incidence rates for gatifloxacin, ciprofloxacin, and levofloxacin were not significantly different. These findings suggest that the increased incidence of CDAD was unrelated to the gatifloxacin formulary change. This pattern could imply an infection prevention issue, other unmeasured confounding variables, or a seasonal variation. Our results demonstrate that limiting DUE analyses to simple pre-versus post-measures potentially produces confusing information, suggesting the need for more detailed patient-level analyses of the impact of formulary changes.
Some studies have reported an increase in the number of CDAD cases when the formulary fluoroquinolone was changed from ciprofloxacin to levofloxacin 10,13 or from levofloxacin to gatifloxacin. 8 In Gaynes et al.'s study of long-term care facility patients, exposure to clindamycin (P = 0.005) and duration of gatifloxacin use (P < 0.001) were independently associated with CDAD. The facility's CDAD rate decreased after levofloxacin replaced gatifloxacin on the formulary, and the authors posited that gatifloxacin is more prone to causing CDAD because it possesses anaerobic coverage that levofloxacin lacks. 8 However, Gaynes et al. did not account for infection control practices that were implemented just prior to switching back to levofloxacin. In addition, the rate of CDAD may have already been increasing prior to the initial formulary change to gatifloxacin. 13 In an analysis of C. difficile infections at a tertiary care teaching hospital, Muto et al. found that the increased incidence of CDAD was associated with the use of levofloxacin, but not with other fluoroquinolones. In addition, the number of cases declined when gatifloxacin and ciprofloxacin replaced levofloxacin on the formulary. 10 Clindamycin (OR 4.8; 95% CI, 1.9-12.0), ceftriaxone (OR 5.4; 95% CI, 1. 8-15.8), and levofloxacin (OR 2.0; 95% CI, 1.2-3.3) were independent risk factors for CDAD. Finally, a retrospective case-control study examined whether an increase in the incidence of CDAD among inpatients and outpatients within the VA health care system in Seattle in 2004 was associated with a formulary change from levofloxacin to gatifloxacin. 25 By analyzing seasonal trends in CDAD rates from 1998 to 2005, the authors concluded that the higher incidence rate following the formulary change was attributable to seasonal variation (higher CDAD rates in the fall and spring each year) and not to increased gatifloxacin use.
Most of our cases of CDAD occurred among inpatients, 65.0% in the pre-change period and 70.2% in the post-change period. This finding is consistent with the literature and not surprising because the primary reservoirs of C. difficile are colonized or infected patients and contaminated environments and objects in the hospital or nursing home. 5 In response to the increase, several of the medical centers implemented additional infection prevention measures to try to decrease the incidence of CDAD. These prevention measures included the following: cleaning the rooms of patients who had CDAD with a 1 : 10 bleach solution upon their discharge from the room, adding a statement to the Contact Precautions signs to wash hands for 15 seconds before exiting the room, educating staff on proper hand hygiene and contact precautions, and monitoring adherence to these practices.
Although episodes of CDAD without prior antibiotic use were not the focus of our evaluation, it is interesting that, in almost one fifth of the episodes of CDAD, there was no record of the patients receiving an antibiotic within the 6 weeks prior to the positive toxin (19.4% in the pre-change period vs. 17.4% in the post-change period). It is possible that these patients received an antibiotic prescription from a non-VA physician, although we did search the medical record for documentation of this information. Perhaps more important, these patients could have acquired CDAD from person-to-person transmission or the environment, or they had other risk factors for CDAD. C. difficile spores remain viable in the environment for years, and contamination can be a problem in hospitals and longterm care facilities. 3 Other risk factors for CDAD can include receipt of chemotherapy, exposure to gastric acid suppressants, advanced age, admission to an intensive care unit, length of hospital stay, and severity of underlying disease. 2,4,5,[26][27][28] Of note, gatifloxacin remained the preferred oral fluoroquinolone in the 10 medical centers until March 2006, when it was replaced by moxifloxacin because of warnings regarding hypoglycemia and hyperglycemia with gatifloxacin. We have not reevaluated our CDAD incidence rate since the change from gatifloxacin to moxifloxacin. There are few published reports of CDAD associated with moxifloxacin, but it has not been prescribed as frequently as levofloxacin or ciprofloxacin. 16,29 However, as the use of moxifloxacin expands within the VA health care system, there is an opportunity to evaluate the incidence of CDAD in a large patient population.

Limitations
Our results should be interpreted with several limitations in mind. First, because this project was conducted as a DUE, we did not collect data on other risk factors for C. difficile colonization, and, therefore, we could not control for the presence of any confounding variables in our analyses, including concomitant antibiotics. Second, we also do not know which strains of C. difficile circulated in the hospitals at that time, or particularly whether there was a new epidemic strain. Third, because we do not know the indication for antibiotics, it is possible that there were differences among the patients that accounted for the selection of a particular fluoroquinolone-namely, patients who received levofloxacin after the change to gatifloxacin as the preferred fluoroquinolone. We did not collect person-level information about either the characteristics or counts of patients receiving antibiotics during our study period. Fourth, relatively small denominators limited the power in our analyses of ciprofloxacin (both time periods) and gatifloxacin (pre-change period). Fifth, given the pre-post design, we might have been observing an ongoing trend in the rate of CDAD (e.g., seasonal variation). 30

■■ Conclusion
After a formulary change from levofloxacin to gatifloxacin as the preferred fluoroquinolone, there was a significant increase in the incidence of CDAD among all antibiotic users and all fluoroquinolone users, but not among users of non-fluoroquinolone antibiotics. However, the CDAD incidence rate for levofloxacin increased significantly from the pre-change period to the postchange period. In the post-change period, the incidence rates for gatifloxacin, ciprofloxacin, and levofloxacin were not significantly different. The increase in CDAD incidence could not be attributed to the addition of gatifloxacin to the formulary, suggesting the influence of other risk factors, infection prevention issues, or a seasonal variation. Limiting DUE analyses to simple pre-versus post-measures may produce misleading information and underscores the need for more detailed assessments, ideally a prospective analysis. Given the concern regarding recent outbreaks of CDAD and the possible association between CDAD and fluoroquinolone use, attention should continue to focus on appropriate antibiotic use and infection prevention measures.

DISCLOSURES
Financial support was provided by the VA Center for Medication Safety. Portions of these results were presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, Orlando, FL, December 8, 2004. Author Chester Good was primarily responsible for the study concept and design, with input from Molly Walbrown, Sherrie Aspinall, and Francesca Cunningham; data collection was the work of Walbrown, Nichole Bayliss, and Cheryl Squier; data interpretation was performed by Walbrown, Aspinall, Good, Bayliss, and Roslyn Stone. Walbrown was primarily responsible for writing the manuscript, with input from Aspinall and Good; and Walbrown, Aspinall, Good, Squier, and Stone revised the manuscript.